Two complementary approaches have been used to examine the mechanisms of retrovirus induced oncogenesis. A) Study of the genetics of oncogenesis by avian retroviruses, and B) Study of the molecular mechanisms of oncogenesis by MoMuLV in mammals. Our results showed that the U3 region of the viral LTR, is the major determinant of the oncogenic potential of the virus. However, other viral sequences determine the virus oncogenic spectrum. In addition, while "promoter insertion" may be important, it does not seem to be the only mechanism by which mammalian retroviruses induce lymphoid malignancies. In this system more than one virus related event may be essential for tumor induction.